低强度迷走神经刺激抑制阻塞性睡眠呼吸暂停兔模型心房颤动的研究
摘要
心房颤动(Atrial Fibrillation,AF)是临床上最常见的持续性心律失常,可引起心力衰竭和动脉栓塞等并发症,导致病人病残率和病死率增加,从而成为一个耗资巨大的公共健康问题。阻塞性睡眠呼吸暂停综合征(Obstructive Sleep Apnea Sydrome, OSAS)是一种常见的慢性呼吸系统疾病,以睡眠时出现反复呼吸暂停、严重打鼾、白天嗜睡为特征。据统计,4%中年男性和2%中年女性患有OSAS。其危险因素诸如年龄、性别、高血压、肥胖等,均与AF相同。近年来越来越多的证据证实阻塞性睡眠呼吸暂停(Obstructive Sleep Apnea,OSA)与AF的发生和维持有重要相关性,并发现伴有OSA的AF病人治疗的成功率明显降低。因此及早发现并积极治疗OSA,对心律失常危险因素的识别和治疗方案的选择提出了新的挑战。然而目前的AF动物模型大多是心房快速起搏、自主神经介导以及左房压力或容积增大导致的AF等,尚缺乏理想的OSA介导的AF模型,本研究第一部分旨在建立一种模拟临床OSA相关的AF的动物模型并研究其特点,为进一步研究OSA并发AF的机制及探索新的治疗方案提供基础。
经导管射频消融术是目前治疗AF的主要方法,然而其复发率高达20%-50%。以往认为,AF消融术后复发率升高与高血压、肥胖、左房增大、持续性AF等因素有关。但近期研究发现,在行导管射频消融术的AF患者中,如果合并OSAS,其复发率要明显高于单纯AF患者,这提示OSAS可能为AF射频消融术后高复发率的另一项危险因素。因此,在合并OSAS和AF患者中导管射频消融的应用受到了一定限制。所以国内外学者一直在试图寻找除消融之外其他治疗AF的非药物方法。自上世纪早期以来,颈部迷走神经干刺激一直被公认为是AF诱发和持续的重要因素之一,其可能的发生机制是使心房有效不应期(Effective Refractory Period, ERP)缩短并增加心房ERP离散度,从而进一步加速多重折返环的形成。但最近一系列相关研究结果表明,低强度迷走神经刺激(Low level vagus nerve stimulation,LLVNS)与阈上刺激不同,有可能是一种预防和治疗AF的有效手段。本研究第二部分旨在研究LLVNS是否能够抑制OSA诱导的AF的发生,并可能为OSA诱导的AF提供一条新的治疗途径。
1. OSAS并发AF的动物模型的建立目的：构建模拟临床OSA相关的AF的动物模型并研究其特点,为进一步研究OSA并发AF的机制及探索新的治疗方案提供基础。
方法：成年新西兰大白兔6只,麻醉后行气管切开并给予气管插管,在呼气末夹闭气管插管1分钟模拟OSA。每间隔5分钟给予一次OSA,6分钟为一个周期,共持续4小时。在OSA之前、之后分别测量ERP、血压、食管内压(ITP)、动脉血气分析(PaO2、PaCO2、PH),在给予OSA的1分钟内通过程序刺激测量ERP和房颤持续时间(Atrial Fibrillation Duration,、AFD)。
结果：每次呼吸暂停1分钟末动脉血二氧化碳分压(PaCO2)较呼吸暂停前即刻明显增加,PH值、动脉血氧分压(Pa02)较呼吸暂停前即刻明显降低,ITP也明显降低。呼吸暂停后心率下降,血压有降低趋势,待呼吸暂停终止后即刻起心率血压明显增加,心率基本恢复至呼吸暂停前状态,而血压较呼吸暂停前明显升高。随着反复OSA的时间延长,ERP逐渐缩短,AFD逐渐延长。
结论：(1)本实验成功构建了一种新的OSAS动物模型。该模型显示了与临床OSAS患者相似的病理生理和电生理特点。
(2)本研究成功模拟了临床OSA相关的AF的动物模型,为进一步研究OSA并发AF的机制及探索新的治疗方案提供了基础。
2. LLVNS抑制OSA兔模型AF的研究
目的：研究LLVNS是否能够抑制OSA诱导的AF的发生,可能为OSA诱导的AF提供一条新的治疗途径。
方法：成年新西兰大白兔22只,麻醉后行气管切开并给予气管插管,在呼气末夹闭气管插管1分钟模拟OSA。每间隔5分钟给予一次OSA,6分钟为一个周期,共持续4小时。在OSA之前、之后分别测量ERP、血压、ITP、PaO2、 PaCO2和PH值,在给予OSA的1分钟内通过程序刺激测量ERP和AFD。实验动物随机分为两组,对照组(control,n=11)只给予呼吸暂停4小时,实验组(LLVNS, n=11)除呼吸暂停外,在起始3小时内同时给予LLVNS,第4小时停止LLVNS,只给予OSA。
结果：本研究发现,对照组随着反复OSA时间的延长,ERP逐渐缩短,AFD逐渐延长。与对照组相比,从第二小时起LLVNS组明显抑制了反复呼吸暂停引起的ERP的缩短(P<0.0001),并且还可以使ERP较基线时延长。同时LLVNS可以显著缩短OSA诱发的AFD。2倍起搏阈值时,LLVNS抑制了由OSA诱发的AF发生,为OSA诱发AF的预防提供了证据。10倍起搏阈值时,在LLVNS组,LLVNS和反复呼吸暂停同步进行1.5小时时,AFD出现明显缩短,至2小时时,LLVNS完全抑制了OSA诱导的AF发作,为OSA诱发AF的治疗提供了证据。LLVNS和OSA同步进行3小时后,停止LLVNS,继续给予反复OSA1小时,ERP仍处于延长状态,且未出现AF发作,这表明3小时LLVNS引起的抗心律失常作用至少可以持续1小时以上。PaO2、PaCO2、PH值、ITP及动脉收缩压(SBP)的变化在两组间无变化。
结论：(1)本研究从设计上高度模拟了临床OSAS的特征,成功构建了OSA诱导的AF模型,并证实LLVNS能够抑制OSA诱导的心房急性电重构,既可以预防也可以治疗OSA引发的AF的发生,为OSA诱发AF的预防和治疗提供了证据。
(2)随着研究的完善,LLVNS完全有潜力运用到临床,成为安全有效治疗AF的方法,为临床治疗AF尤其是OSA诱发的AF提供一种新的治疗选择。
Atrial fibrillation (AF) is the most common and sustained cardiac arrhythmia in clinic, which can induce many complications, such as heart failure, arterial thrombosis, etc. At present AF has become a costly public health problem for its high morbidity and mortality. Obstructive sleep apnea syndrome (OSAS) is a commonly encountered chronic respiratory disease occurring repeatedly during sleep, characterized by apnea, severe snoring and daytime sleepiness. According to statistics,4%of middle-aged men and2%of middle-aged women suffer from obstructive sleep apnea (OSA). The risk factors of OSA, such as age, sex, hypertension, obesity, etc. are the same as AF. In recent years, cumulative evidences have showed that OSA has an important correlation with the occurrence and maintenance of AF, and the therapy effect of AF patients in complication with OSA was significantly reduced as compared to that of AF patients without OSA. The treatment of AF is faced with new challenge. At present most of the current animal models of AF are established by rapid atrial pacing, mediated by the autonomic nervous and left atrial pressure or volume elevation, the ideal OSA-mediated AF model is not well established. It is important to establish an effective animal model of AF related to OSA. The first part of this study aimed to establish an OSA-related AF animal model, study its electrophysiological characteristics, and explore the possible mechanisms of OSA-induced concurrent AF, which may provide a new treatment method for AF complicated with OSA.
Radiofrequency catheter ablation is currently the main strategy for AF treatment, but its recurrence rate reaches up to20%to50%. It was once believed that the recurrence rate of AF after ablation was associated with elevated blood pressure, obesity, left atrial enlargement, persistent atrial fibrillation and other factors. But recent studies have found that the recurrence rate is significantly higher in patients concomitant with AF and OSAS than that with AF only, suggesting that OSAS may be another risk factor for high recurrence rate in AF therapy. Thus, the application of catheter ablation is subjected to certain restriction in AF patients combined with OSAS. Therefore, scholars have been trying to find a non-drug and non-ablation therapy for AF. Since the early20th century, cervical vagus nerve stimulation has been recognized as one of the important factors for the induction and sustain of AF. The possible underling mechanism of cervical vagus nerve stimulation was to shorten the atrial effective refractory period and increase its dispersion, thereby accelerating the formation of multiple reentrant loop. But a series of recent research results indicate that low-intensity vagal nerve stimulation, which is different with a threshold stimulus, may be an effective means for the prevention and treatment of AF. The second part of this research is to study whether low-intensity vagus nerve stimulation could suppress the occurrence of OSA-induced AF, which would provide a new therapeutic approach for OSA-induced AF.
Objective:This study is to establish a new animal model of atrial fibrillation (AF) associated with obstructive sleep apnea (OSA).
Methods:Six rabbits were anesthetized and received a tracheostomy. The tracheal intubation was clamped at the end of expiration for1minute to simulate OSA. Over a period of4hours, OSA was delivered every6minutes. Effective refractory period (ERP), blood pressure, intraesophageal pressure, PH value, arterial oxygen pressure (PaO2) and partial pressure of carbon dioxide in arterial blood (PaCO2) were measured before and after each regular intervals of OSA. AF duration (AFD) and ERP were measured by programmed stimulation.
Results:PH value, PaO2and intraesophageal pressure significantly decreased at the end of OSA, and PaCO2obviously increased compared with that before OSA. During OSA, heart rate and blood pressure in rabbits decreased gradually. However, there was no significant difference compared with that before OSA. Once OSA disappeared, heart rate and blood pressure dramatically increased, with heart rate almost returning to that before OSA, and blood pressure higher than that before OSA. Along with the extension of OSA time, ERP was shortened and the duration of AF gradually increased.
Conclusion:Our study successfully established an experimental animal model that simulated AF associated with OSA, which showed the similar characteristics in pathophysiology and electrophysiology with clinical patients. This may provide experimental data for studying the mechanism and developing new therapeutic methods for AF associated with OSA.
Introduction:Atrial fibrillation (AF) is highly associated with obstructive sleep apnea (OSA) in which AF is triggered by a surge of the cardiac autonomic nervous system (CANS). Prior studies have showed that low level vagus nerve stimulation (LLVNS), at voltages not slowing sinus rate or AV conduction, can alleviate AF by suppressing the electrical activity of CANS. This study want to investigate if LLVNS deliver at the right cervical vagosympathetic trunk can suppress AF in a rabbit model of OSA.
Methods:All22rabbits received a tracheostomy. The endotracheal tube was clamped at the end of expiration for1minute to simulate OSA. Over a period of4hours, OSA was delivered every6minutes. Effective refractory period (ERP), blood pressure, intraesophageal pressure and blood gas (PaO2, PaCO2and pH) were measured before and after each episode of OSA. AF duration (AFD) and ERP were measured by programmed stimulation. LLVNS group rabbits (n=11) received LLVNS in the first3hours of the study. LLVNS deliver was stopped from the beginning of the fourth hour. Control group rabbits (n=11) only received OSA.
Results:With the extension of OSA time, ERP was shortened and the duration of AF (AFD) was gradually increased in control group as compared to its base level. Compared with control group, from the second hour, LLVNS could obviously prolong ERP (P<0.0001), shorten OSA-induced AFD. During the stimulation with2diastolic threshold, LLVNS significantly inhibited the occurrence of AF induced by OSA.1.5hour later after the concomitant treatment of LLVNS at10diastolic threshold plus OSA, AFD was obviously shortened in LLVNS group, compared with control group. At the end of second hour, LLVNS completely suppressed OSA-induced AF.3hours after concomitant treatment, LLVNS was stopped and OSA was maintained for another1hour, ERP was still prolonged as compared to control group, and there had no occurrence of AF, suggesting the anti-arrhythmia effect of3hours LLVNS could sustain for more than1hour. The blood pH, PaO2, PaCO2level, the intraesophageal pressure and the hypertensive response during OSA were not different between the two groups.
Conclusion:LLVNS can suppress ERP shortening and AF induced by OSA. LLVNS may serve as new therapeutic approach to treat OSA-induced AF.
经导管射频消融术是目前治疗AF的主要方法,然而其复发率高达20%-50%。以往认为,AF消融术后复发率升高与高血压、肥胖、左房增大、持续性AF等因素有关。但近期研究发现,在行导管射频消融术的AF患者中,如果合并OSAS,其复发率要明显高于单纯AF患者,这提示OSAS可能为AF射频消融术后高复发率的另一项危险因素。因此,在合并OSAS和AF患者中导管射频消融的应用受到了一定限制。所以国内外学者一直在试图寻找除消融之外其他治疗AF的非药物方法。自上世纪早期以来,颈部迷走神经干刺激一直被公认为是AF诱发和持续的重要因素之一,其可能的发生机制是使心房有效不应期(Effective Refractory Period, ERP)缩短并增加心房ERP离散度,从而进一步加速多重折返环的形成。但最近一系列相关研究结果表明,低强度迷走神经刺激(Low level vagus nerve stimulation,LLVNS)与阈上刺激不同,有可能是一种预防和治疗AF的有效手段。本研究第二部分旨在研究LLVNS是否能够抑制OSA诱导的AF的发生,并可能为OSA诱导的AF提供一条新的治疗途径。
1. OSAS并发AF的动物模型的建立目的：构建模拟临床OSA相关的AF的动物模型并研究其特点,为进一步研究OSA并发AF的机制及探索新的治疗方案提供基础。
方法：成年新西兰大白兔6只,麻醉后行气管切开并给予气管插管,在呼气末夹闭气管插管1分钟模拟OSA。每间隔5分钟给予一次OSA,6分钟为一个周期,共持续4小时。在OSA之前、之后分别测量ERP、血压、食管内压(ITP)、动脉血气分析(PaO2、PaCO2、PH),在给予OSA的1分钟内通过程序刺激测量ERP和房颤持续时间(Atrial Fibrillation Duration,、AFD)。
结果：每次呼吸暂停1分钟末动脉血二氧化碳分压(PaCO2)较呼吸暂停前即刻明显增加,PH值、动脉血氧分压(Pa02)较呼吸暂停前即刻明显降低,ITP也明显降低。呼吸暂停后心率下降,血压有降低趋势,待呼吸暂停终止后即刻起心率血压明显增加,心率基本恢复至呼吸暂停前状态,而血压较呼吸暂停前明显升高。随着反复OSA的时间延长,ERP逐渐缩短,AFD逐渐延长。
结论：(1)本实验成功构建了一种新的OSAS动物模型。该模型显示了与临床OSAS患者相似的病理生理和电生理特点。
(2)本研究成功模拟了临床OSA相关的AF的动物模型,为进一步研究OSA并发AF的机制及探索新的治疗方案提供了基础。
2. LLVNS抑制OSA兔模型AF的研究
目的：研究LLVNS是否能够抑制OSA诱导的AF的发生,可能为OSA诱导的AF提供一条新的治疗途径。
方法：成年新西兰大白兔22只,麻醉后行气管切开并给予气管插管,在呼气末夹闭气管插管1分钟模拟OSA。每间隔5分钟给予一次OSA,6分钟为一个周期,共持续4小时。在OSA之前、之后分别测量ERP、血压、ITP、PaO2、 PaCO2和PH值,在给予OSA的1分钟内通过程序刺激测量ERP和AFD。实验动物随机分为两组,对照组(control,n=11)只给予呼吸暂停4小时,实验组(LLVNS, n=11)除呼吸暂停外,在起始3小时内同时给予LLVNS,第4小时停止LLVNS,只给予OSA。
结果：本研究发现,对照组随着反复OSA时间的延长,ERP逐渐缩短,AFD逐渐延长。与对照组相比,从第二小时起LLVNS组明显抑制了反复呼吸暂停引起的ERP的缩短(P<0.0001),并且还可以使ERP较基线时延长。同时LLVNS可以显著缩短OSA诱发的AFD。2倍起搏阈值时,LLVNS抑制了由OSA诱发的AF发生,为OSA诱发AF的预防提供了证据。10倍起搏阈值时,在LLVNS组,LLVNS和反复呼吸暂停同步进行1.5小时时,AFD出现明显缩短,至2小时时,LLVNS完全抑制了OSA诱导的AF发作,为OSA诱发AF的治疗提供了证据。LLVNS和OSA同步进行3小时后,停止LLVNS,继续给予反复OSA1小时,ERP仍处于延长状态,且未出现AF发作,这表明3小时LLVNS引起的抗心律失常作用至少可以持续1小时以上。PaO2、PaCO2、PH值、ITP及动脉收缩压(SBP)的变化在两组间无变化。
结论：(1)本研究从设计上高度模拟了临床OSAS的特征,成功构建了OSA诱导的AF模型,并证实LLVNS能够抑制OSA诱导的心房急性电重构,既可以预防也可以治疗OSA引发的AF的发生,为OSA诱发AF的预防和治疗提供了证据。
(2)随着研究的完善,LLVNS完全有潜力运用到临床,成为安全有效治疗AF的方法,为临床治疗AF尤其是OSA诱发的AF提供一种新的治疗选择。
Atrial fibrillation (AF) is the most common and sustained cardiac arrhythmia in clinic, which can induce many complications, such as heart failure, arterial thrombosis, etc. At present AF has become a costly public health problem for its high morbidity and mortality. Obstructive sleep apnea syndrome (OSAS) is a commonly encountered chronic respiratory disease occurring repeatedly during sleep, characterized by apnea, severe snoring and daytime sleepiness. According to statistics,4%of middle-aged men and2%of middle-aged women suffer from obstructive sleep apnea (OSA). The risk factors of OSA, such as age, sex, hypertension, obesity, etc. are the same as AF. In recent years, cumulative evidences have showed that OSA has an important correlation with the occurrence and maintenance of AF, and the therapy effect of AF patients in complication with OSA was significantly reduced as compared to that of AF patients without OSA. The treatment of AF is faced with new challenge. At present most of the current animal models of AF are established by rapid atrial pacing, mediated by the autonomic nervous and left atrial pressure or volume elevation, the ideal OSA-mediated AF model is not well established. It is important to establish an effective animal model of AF related to OSA. The first part of this study aimed to establish an OSA-related AF animal model, study its electrophysiological characteristics, and explore the possible mechanisms of OSA-induced concurrent AF, which may provide a new treatment method for AF complicated with OSA.
Radiofrequency catheter ablation is currently the main strategy for AF treatment, but its recurrence rate reaches up to20%to50%. It was once believed that the recurrence rate of AF after ablation was associated with elevated blood pressure, obesity, left atrial enlargement, persistent atrial fibrillation and other factors. But recent studies have found that the recurrence rate is significantly higher in patients concomitant with AF and OSAS than that with AF only, suggesting that OSAS may be another risk factor for high recurrence rate in AF therapy. Thus, the application of catheter ablation is subjected to certain restriction in AF patients combined with OSAS. Therefore, scholars have been trying to find a non-drug and non-ablation therapy for AF. Since the early20th century, cervical vagus nerve stimulation has been recognized as one of the important factors for the induction and sustain of AF. The possible underling mechanism of cervical vagus nerve stimulation was to shorten the atrial effective refractory period and increase its dispersion, thereby accelerating the formation of multiple reentrant loop. But a series of recent research results indicate that low-intensity vagal nerve stimulation, which is different with a threshold stimulus, may be an effective means for the prevention and treatment of AF. The second part of this research is to study whether low-intensity vagus nerve stimulation could suppress the occurrence of OSA-induced AF, which would provide a new therapeutic approach for OSA-induced AF.
Objective:This study is to establish a new animal model of atrial fibrillation (AF) associated with obstructive sleep apnea (OSA).
Methods:Six rabbits were anesthetized and received a tracheostomy. The tracheal intubation was clamped at the end of expiration for1minute to simulate OSA. Over a period of4hours, OSA was delivered every6minutes. Effective refractory period (ERP), blood pressure, intraesophageal pressure, PH value, arterial oxygen pressure (PaO2) and partial pressure of carbon dioxide in arterial blood (PaCO2) were measured before and after each regular intervals of OSA. AF duration (AFD) and ERP were measured by programmed stimulation.
Results:PH value, PaO2and intraesophageal pressure significantly decreased at the end of OSA, and PaCO2obviously increased compared with that before OSA. During OSA, heart rate and blood pressure in rabbits decreased gradually. However, there was no significant difference compared with that before OSA. Once OSA disappeared, heart rate and blood pressure dramatically increased, with heart rate almost returning to that before OSA, and blood pressure higher than that before OSA. Along with the extension of OSA time, ERP was shortened and the duration of AF gradually increased.
Conclusion:Our study successfully established an experimental animal model that simulated AF associated with OSA, which showed the similar characteristics in pathophysiology and electrophysiology with clinical patients. This may provide experimental data for studying the mechanism and developing new therapeutic methods for AF associated with OSA.
Introduction:Atrial fibrillation (AF) is highly associated with obstructive sleep apnea (OSA) in which AF is triggered by a surge of the cardiac autonomic nervous system (CANS). Prior studies have showed that low level vagus nerve stimulation (LLVNS), at voltages not slowing sinus rate or AV conduction, can alleviate AF by suppressing the electrical activity of CANS. This study want to investigate if LLVNS deliver at the right cervical vagosympathetic trunk can suppress AF in a rabbit model of OSA.
Methods:All22rabbits received a tracheostomy. The endotracheal tube was clamped at the end of expiration for1minute to simulate OSA. Over a period of4hours, OSA was delivered every6minutes. Effective refractory period (ERP), blood pressure, intraesophageal pressure and blood gas (PaO2, PaCO2and pH) were measured before and after each episode of OSA. AF duration (AFD) and ERP were measured by programmed stimulation. LLVNS group rabbits (n=11) received LLVNS in the first3hours of the study. LLVNS deliver was stopped from the beginning of the fourth hour. Control group rabbits (n=11) only received OSA.
Results:With the extension of OSA time, ERP was shortened and the duration of AF (AFD) was gradually increased in control group as compared to its base level. Compared with control group, from the second hour, LLVNS could obviously prolong ERP (P<0.0001), shorten OSA-induced AFD. During the stimulation with2diastolic threshold, LLVNS significantly inhibited the occurrence of AF induced by OSA.1.5hour later after the concomitant treatment of LLVNS at10diastolic threshold plus OSA, AFD was obviously shortened in LLVNS group, compared with control group. At the end of second hour, LLVNS completely suppressed OSA-induced AF.3hours after concomitant treatment, LLVNS was stopped and OSA was maintained for another1hour, ERP was still prolonged as compared to control group, and there had no occurrence of AF, suggesting the anti-arrhythmia effect of3hours LLVNS could sustain for more than1hour. The blood pH, PaO2, PaCO2level, the intraesophageal pressure and the hypertensive response during OSA were not different between the two groups.
Conclusion:LLVNS can suppress ERP shortening and AF induced by OSA. LLVNS may serve as new therapeutic approach to treat OSA-induced AF.
引文
1. Braunwald E. Shattuck lecture--cardiovascular medicine at the turn of the millennium:triumphs, concerns, and opportunities. The New England journal of medicine.1997;337:1360-1369.
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4. Bounhoure JP, Galinier M, Didier A, et al. Sleep apnea syndromes and cardiovascular disease. Bulletin de Academie nationale de medecine. 2005;189:445-459; discussion 60-64.
5. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea:a population health perspective. American journal of respiratory and critical care medicine.2002;165:1217-1239.
6.李蔚,江程澄.阻塞性睡眠呼吸暂停综合征患者持续正压通气治疗后血清细胞因子的变化.中国老年学杂志.2013；33：1559-1563.
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1. Young T, Palta M, Dempsey J, et al. The occurrence o f sleep disordered breathing among middle aged adults. N Eng 1 JM ed.1993;328:1230-1235.
2. Engleman HM, Douglas NJ. Sleepiness, cognitive function, and quality of life in obstructive sleep apnoea/hypopnoea syndrome. Thorax.2004;59:618-622.
3. Johns MW. A new method for measuring daytime sleepiness:the Epworth sleepiness scale. Sleep.1991; 14:540-545.
4. Netzer NC, Stoohs RA, Netzer CM, et al. Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med.1999; 131:485-491.
5. Abrishami A, Khajehdehi A, Chung F. A systematic review of screening questionnaires for obstructive sleep apnea. Can J Anaesth.2010; 57:423-438.
6. Guilleminault C, Conolly SJ, Winkle RA, et al. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol.1983;52:490-494.
7. Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation.1998;97:2154-2159.
8. Sin DD, Fitzgerald F, Parker JD, et al. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med.1999; 160:1101-1106.
9. Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing:The Sleep Heart Health Study. Am J Respir Crit Care Med.2006; 173:910-916.
10. Mooe T, Gullsby S, Rabben T, et al. Sleep-disordered breathing:a novel predictor of atrial fibrillation after coronary artery bypass surgery. Coron Artery Dis.1996; 7: 475-478.
11. Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation.2004; 110:364-367.
12. Porthan KM, Melin JH, Kupila JT, et al. Prevalence of sleep apnea syndrome in lone atrial fibrillation:a case-control study. Chest.2004;125:879-885.
13. Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation.Circulation.2003; 107:2589-2594.
14. Jongnarangsin K, Chugh A, Good E, et al. Body mass index, obstructive sleep apnea, and outcomes of catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol.2008; 19:668-672.
15. Monahan K, Brewster J, Wang L, et al. Relation of the severity of obstructive sleep apnea in response to anti-arrhythmic drugs in patients with atrial fibrillation or atrial flutter. Am J Cardiol.2012;110:369-372.
16. Shivalkar B, Van de Heyning C, Kerremans M, et al. Obstructive sleep apnea syndrome:more insights on structural and functional cardiac alterations, and the effects of treatment with continuous positive airway pressure. J Am Coll Cardiol. 2006;47:1433-1439.
17. Drager LF, Polotsky VY, Lorenzi-Filho G, et al. Obstructive sleep apnea:an emerging risk factor for atherosclerosis. Chest.2011;140:534-542.
18. Caples SM, Somers VK. Sleep-disordered breathing and atrial fibrillation. Prog Cardiovasc Dis.2009;51:411-415.
19. Jais P, Haissaguerre M, Shah DC, et al. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation.1997;95:572-576.
20. Maeno K, Kasai T, Kasagi S, et al. Relationship between atrial conduction delay and obstructive sleep apnea. Heart Vessels.2013;28:639-645.
21. Maeno K, Kasagi S, Ueda A, et al. Effects of obstructive sleep apnea and its treatment on signal-averaged P-wave duration in men. Circ Arrhythm Electrophysiol.2013;6:287-293.
22. Watanabe E, Arakawa T, Uchiyama T, et al. High sensitivity Creactiveprotein is predictive of successful cardioversion for atrialfibrillation and maintenance of sinus rhythm after conversion. Int J Cardiol.2006;108:346-353.
23. Marin F, Corral J, Roldan V, et al. Factor X III Va134 Leu polymorphism modulates the prothrombotic and inflammatory state associated with atrial fibrillation. J Mol Cell Cardiol.2004;37:699-704.
24. Gershov D, Kim S, Brot N, et al. C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinfl ammatory innate immune response:implications for systemic autoimmunity. J Exp.Med.2000; 192:1353-1364.
25. Yokoe T, Minoguehi K, Matsuo H, et al. Elevated levels of C-reaetive protein and interieukin-6 in patients with obstruetive sleep apnea syndrome are decreased by nasal continuous positive airway Pressure. Circulation.2003;107:1129-1134.
26. Chung S, Yoon IY, Shin YK, et al. Endothelial dysfunction and C-reactive protein in relation with the severity of obstructive sleep apnea syndrome. Sleep. 2007;30:997-1001.
27. Minoehi K, TaZaki T, Yokoe T, et al. Elevated production of tumor necrosis factor-alpha by monoeytes in patients with obstructive sleep apnea syndrome. Chest.2004;126:1473-1479.
28. Darko DF, Miller JC, Gallen C, et al. Sleep electroenecephalogram delta frequency amplitude, night plasma levels of tumor necrosis factor alpha, and human immunodeficiency virus infeetion.Proc Natl Acad Sci USA.1995;92: 120802-120804.
29. Tan KC, Chow WS, Lam JC, et al. HDL dysfunction in obstructive sleep apnea. Atherosclerosis.2006; 184:377-382.
30. Caragnano GE, Kharitonov SA, Resta O, et al.8-Isoprostane, a marker of oxidative stress, is increased in exhaled breathe condensate of patients with obstructive sleep apnea after night and is reduced by continuous positive airway pressure therapy. Chest.2003; 124:1356-1392.
2. Wolf PA, Benjamin EJ, Belanger AJ, et al. Secular trends in the prevalence of atrial fibrillation:The Framingham Study. American heart journal. 1996;131:790-795.
3. Calkins H, Brugada J, Packer DL, et al. HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation developed in partnership with the European Heart Rhythm Association (EHRA) and the European Cardiac Arrhythmia Society (ECAS); in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), and the Society of Thoracic Surgeons (STS). Endorsed and approved by the governing bodies of the American College of Cardiology, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, and the Heart Rhythm Society. Europace:European pacing, arrhythmias, and cardiac electrophysiology:journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2007;9:335-379.
4. Bounhoure JP, Galinier M, Didier A, et al. Sleep apnea syndromes and cardiovascular disease. Bulletin de Academie nationale de medecine. 2005;189:445-459; discussion 60-64.
5. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea:a population health perspective. American journal of respiratory and critical care medicine.2002;165:1217-1239.
6.李蔚,江程澄.阻塞性睡眠呼吸暂停综合征患者持续正压通气治疗后血清细胞因子的变化.中国老年学杂志.2013；33：1559-1563.
7. Johns MW. A new method for measuring daytime sleepiness:the Epworth sleepiness scale. Sleep.1991; 14:540-545.
8. Netzer NC, Stoohs RA, Netzer CM, et al.Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med.1999; 131:485-491.
9. Abrishami A, Khajehdehi A, Chung F. A systematic review of screening questionnaires for obstructive sleep apnea. CanJ Anaesth.2010; 57:423-438.
10. Guilleminault C, Conolly SJ, Winkle RA, et al. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol.1983;52:490-494.
11. Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation.1998;97:2154-2159.
12. Sin DD, Fitzgerald F, Parker JD, et al. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med.1999;160:1101-1106.
13. Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing:The Sleep Heart Health Study. Am J Respir Crit Care Med.2006;173:910-916.
14. Mooe T, Gullsby S, Rabben T, et al. Sleep-disordered breathing:a novel predictor of atrial fibrillation after coronary artery bypass surgery. Coron Artery Dis.1996; 7:475-478.
15. Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation.2004;110.:364-367.
16. Porthan KM, Melin JH, Kupila JT, et al. Prevalence of sleep apnea syndrome in lone atrial fibrillation:a case-control study. Chest.2004; 125:879-885.
17. Shivalkar B, Van de Heyning C, Kerremans M, et al. Obstructive sleep apnea syndrome:more insights on structural and functional cardiac alterations, and the effects of treatment with continuous positive airway pressure. J Am Coll Cardiol. 2006;47:1433-1439.
18. Drager LF, Polotsky VY, Lorenzi-Filho G, et al. Obstructive sleep apnea:an emerging risk factor for atherosclerosis. Chest.2011;140:534-542.
19. Caples SM, Somers VK.Sleep-disordered breathing and atrial fibrillation. Prog Cardiovasc Dis.2009;51:411-415.
20. Jais P, Haissaguerre M, Shah DC, et al. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation.1997;95:572-576.
21. Maeno K, Kasai T, Kasagi S, et al. Relationship between atrial conduction delay and obstructive sleep apnea. Heart Vessels.2013;28:639-645.
22. Maeno K, Kasagi S, Ueda A, et al. Effects of obstructive sleep apnea and its treatment on signal-averaged P-wave duration in men. Circ Arrhythm Electrophysiol.2013;6:287-293.
23. Watanabe E, Arakawa T, Uchiyama T, et al. High sensitivity Creactiveprotein is predictive of successful cardioversion for atrialfibrillation and maintenance of sinus rhythm after conversion. Int Jcardiol.2006;108:346-353.
24. Marin F, Corral J, Roldan V, et al. Factor Ⅹ Ⅲ Va134 Leu polymorphism modulates the prothrombotic and inflammatory state associated with atrial fibrillation. J Mol Cell Cardiol.2004;37:699-704.
25. Gershov D, Kim S, Brot N, et al. C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinfl ammatory innate immune response:implications for systemic autoimmunity. J Exp Med.2000; 192:1353-1364.
26. Yokoe T, Minoguehi K, Matsuo H, et al. Elevated levels of C-reaetive protein and interieukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway Pressure. Circulation.2003; 107: 129-1134
27. Chung S, Yoon IY, Shin YK, et al. Endothelial dysfunction and C-reactive protein in relation with the severity of obstructive sleep apnea syndrome. Sleep. 2007;30:997-1001.
28. Minoehi K, TaZaki T, Yokoe T, et al. Elevated production of tumor necrosis factor-alpha by monoeytes in patients with obstructive sleep apnea syndrome. Chest.2004;126:1473-1479.
29. Darko DF, Miller JC, Gallen C, et al. Sleep electroenecephalogram delta frequency amplitude, night plasma levels of tumor necrosis factor alpha, and human immunodeficiency virus infeetion.Proc Natl Acad Sci USA.1995;92: 120802-120804.
30. Tan KC, Chow WS, Lam JC, et al. HDL dysfunction in obstructive sleep apnea. Atherosclerosis.2006; 184:377-382.
31. Caragnano GE, Kharitonov SA, Resta O, et al.8-Isoprostane, a marker of oxidative stress, is increased in exhaled breathe condensate of patients with obstructive sleep apnea after night and is reduced by continuous positive airway pressure therapy. Chest.2003;124:1356-1392.
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